The present invention relates to novel compounds, pharmaceutical compositions containing said compounds and to methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsey, irritable bowl syndrome, immune supression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence demonstrating that CRF may also play a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data has demonstrated that CRF may have implications in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist xcex1-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
In order to study these specific cell-surface receptor proteins, compounds must be identified which can interact with the CRF receptor in a specific manner dictated by the pharmacological profile of the characterized receptor. Toward that end, there is evidence that the direct CRF antagonist compounds and compositions of this invention; that can attenuate the physiological responses to stress-related disorders, will have potential therapeutic utility for the treatment of depression and anxiety-related disorders. All of the aforementioned references are hereby incorporated by reference.
PCT Application US94/1105 teaches 1N-alkyl-N-arylpyrimidines and derivatives thereof in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsey, irritable bowl syndrome, immune supression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems.
U.S. Pat. No. 5,062,882 teaches the synthesis of aryloxy- and arylthiotriazines useful as herbicides.
U.S. Pat. Nos. 4,427,437 and 4,460,588 describe the synthesis of aryloxy- and arylthiopyrimidines useful for the killing of internal parasites, especially trematodes and nematodes, in warm blooded animals, and/or as herbicides for inhibiting the growth of severely damaging or killing plants.
U.S. Pat. No. 5,281,707 teaches the synthesis and utility of water-soluble aryloxy triazines, useful for the thermal and photochemical stabilization of polyamide fiber materials
The compounds and methods of the present invention provide the methodology for the production of specific high-affinity compounds capable of inhibiting the action of CPF at its receptor protein in the brain. These compounds would be useful in the treatment of a variety of neurodegenerative, neuropsychiatric and stress-related disorders. It is further asserted that this invention may provide compounds and pharmaceutical compositions suitable for use in such a method. Further advantages of this invention will be clear to one skilled in the art from the reading of the description that follows.
The present invention relates to novel 2-aryloxy- and 2-arylthiosubstituted pyrimidines and triazines and derivatives thereof, pharmaceutical compositions containing such compounds and method of using them in the treatment affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsey, irritable bowl syndrome, immune supression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. Said compounds interact with and have antagonist activity at the CRF receptor and thus have therapeutic effect.
[1] This invention provides compounds of formula (I): 
xe2x80x83or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q=O, S(O)n;
R1 is C1-C4-alkyl, -alkenyl, -alkynyl, C1-C2 haloalkyl, halogen, NR6R7, OR8, SR8, CN;
R3 is C1-C8 alkyl, C1-C2 haloalkyl, halogen, NR6R7, OR8, SR8,(CH2)kNR6R7, (CH2)kOR8, CH(CHR16CHR16OR8)2, CH(CN)AR, CH(CN)2, CHR16(CHR16)pOR8, (CHR16)pAr wherein the aryl group is substituted with 1-3 R18, (CHR16)pheteroaryl wherein the heteroaryl group is substituted with 1-3 R18, 1-tetrahydroquinolinyl, 2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with 0-3 groups chosen from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, cyano, S(O)z-(C1-C6)alkyl;
V is N;
Y is CR2 or N;
Z is N;,
R2 and is independently selected at each occurrence from the group consisting of hydrogen, halo, halomethyl, methyl cyano, nitro, NR6R7, NH(COR9), N(COR9);
X and Xxe2x80x2 are independently selected at each occurrence from the group consisting of alkyl, halogen, S(O)nR8, OR8, halomethyl, NR14R15, CN;
R5 is H, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C3 haloalkyl, C1-C6 alkoxy, (CHR16)pOR8, (CHR16)pS(O)nR8, (CHR16)pNR14R15, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, CN;
R6 and R7 are independently selected at each occurrence from the group consisting of:
hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, CH(R16) (CHR16)pOR8, (CHR16)pOR8, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from the following:
hydrogen,
halogen,
C1-C6 alkyl,
C1-C6 alkoxy,
amino,
NHC(xe2x95x90O) (C1-C6 alkyl),
NH(C1-C6 alkyl)
N(C1-C6 alkyl)2,
nitro,
CO2(C1-C6 alkyl),
cyano,
S(O)zxe2x80x94(C1-C6-alkyl), or
R6 and R7 can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-3 R17,
or, when considered with the commonly attached nitrogen, R6 and R7 can be taken together to form a heterocycle,
said heterocycle being substituted on carbon with 1-3 groups consisting of:
hydrogen,
C1-C6 alkyl,
(C1-C6)alkyl(C1-C4)alkoxy, hydroxy, or
C1-C6 alkoxy;
A is CH2, O, S(O)n, N(C(xe2x95x90O)R24), N(R19), C(H) (NR14R15), C(H) (OR20), C(H) (C(xe2x95x90O) R21), N(S(O)nR21);
R8 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)tR22, C3-C10 cycloalkyl, cycloalkylalkyl, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from the following:
hydrogen,
halogen,
C1-C6 alkyl
C1-C6 alkoxy,
amino,
NHC(xe2x95x90O) (C1-C6 alkyl),
NH(C1-C6 alkyl)
N(C1-C6 alkyl)2,
nitro,
CO2(C1-C6 alkyl),
cyano;
S(O)z(C1-C6-alkyl);
R9 is independently selected at each occurrence from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, aryl substituted with 0-3 R18, and xe2x80x94(C1-C6 alkyl)-aryl substituted with 0-3 R18;
R14 and R15 are independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)tR22, aryl substituted with 0-3 R18;
R16 is hydrogen or C1-C4 alkyl;
R17 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halo, OR23, SR23, NR23R24 (C1-C6) alkyl, (C1-C4) alkoxy;
R18 is hydrogen, C1-C4 alkyl, C1-C2 haloalkyl, C1-C4 alkoxy, C(xe2x95x90O)R24, NO2, halogen or cyano;
R19 is C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)wR22, aryl substituted with 0-3 R18;
R20 is hydrogen, C(xe2x95x90O)R22, C1-C4 alkyl, C2-C4 alkenyl;
R21 is hydrogen, C1-C4 alkoxy, NR23R24, hydroxyl or C1-C4 alkyl;
R22 is cyano, OR24, SR24, NR23R24, C3-C6 cycloalkyl;
R23 and R24 are independently selected at each occurrence from hydrogen or C1-C4 alkyl;
k is 1-4;
n is independently selected at each occurrence from 0-2;
p is 0-3;
q is 0-3;
r is 1-4;
t is independently selected at each occurrence from 1-6;
z=0-3;
w=1-6;
provided, however, that when Y is CR2, then R3 is (CHR16)pAr wherein the aryl group is substituted with 1-3 R1 or (CHR16)pheteroaryl wherein the heteroaryl group is substituted with 1-3 R18.
[2] Preferred are those compounds of claim 1 wherein:
R3 is C1-C4 alkyl, C1-C2 haloalkyl, NR6R7, OR8, CH(CHR16CHR16OR8)2, CH(CN)AR, CH(CN)2, CH(R16CHR16)pOR8, (CHR16)pAr wherein the aryl group is substituted with 1-3 R18, (CHR16)pheteroaryl wherein the heteroaryl group is substituted with 1-3 R18, 1-tetrahydroquinolinyl, 2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with 0-3 groups chosen from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, cyano, S(O)z-(C1-C6)alkyl;
R2 is independently selected at each occurrence from the group consisting of hydrogen, halo, methyl, nitro, cyano, NR6R7, NH(COR9), N(COR9)2;
R6 and R7 are independently selected at each occurrence from the group consisting of:
hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, cycloalkylalkyl, C1-C6 alkoxy, (CHR16)pOR8, (CHR16)pOR8, xe2x80x94(C1-C6 alkyl)-aryl, heteroaryl, xe2x80x94(C1-C6 alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from the following:
hydrogen,
halogen,
C1-C6 alkyl,
C1-C6 alkoxy,
NHC(xe2x95x90O)(C1-C6 alkyl),
NH(C1-C6 alkyl)
N(C1-C6 alkyl)2,
CO2(C1-C6 alkyl),
cyano,
or R6 and R7 can be taken together to form xe2x80x94(CH2)qA(CH2)rxe2x80x94, optionally substituted with 0-3 R17,
or, when considered with the commonly attached nitrogen, R6 and R7 can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of:
hydrogen,
C1-C6 alkyl,
(C1-C6)alkyl(C1-C4)alkoxy,
hydroxy, or
C1-C6 alkoxy;
R8 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)tR22, C3-C10 cycloalkyl, cycloalkylalkyl, xe2x80x94(C1-C6 alkyl)-aryl, or hetero-aryl optionally substituted with 1-3 groups selected from the following:
hydrogen,
halogen,
C1-C6 alkyl
C1-C6 alkoxy,
NHC(xe2x95x90O)(C1-C6 alkyl),
NH(C1-C6 alkyl)
N(C1-C6 alkyl)2,
CO2(C1-C6 alkyl);
R14 and R15 are independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;
R17 is hydrogen, C1-C4 alkyl, C1C4 alkoxy, (C1-C6)alkyl(C1-C4)alkoxy;
R18 is hydrogen, C1-C4 alkyl, C1-C2 haloalkyl, C1-C4 alkoxy, or cyano;
R19 is C1-C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R18;
R22 is cyano, OR24, SR24, NR23R24, C3-C6 alkyl or cycloalkyl;
R23 and R24 are independently selected at each occurrence from hydrogen or C1-C4 alkyl;
t is independently selected at each occurrence from 1-3;
w is 1-3;
provided, however, that when Y is CR2, then R3 is (CHR16)pAr wherein the aryl group is substituted with 1-3 R18 or (CHR16)pheteroaryl wherein the heteroaryl group is substituted with 1-3 R18.
[3] More preferred are those compounds of claim 2 wherein:
R1 is C1-C2 alkyl, halide, NR6R7, OR8;
R3 is C1-C4 alkyl, C1-C2 haloalkyl, NR6R7, OR8, (CH2)kNR6R7, (CH2)kOR8;
Y is N;
X and Xxe2x80x2 are independently selected at each occurrence from the group consisting of methyl, hydrogen, Cl, Br, I, OR8, NR14R15, CN, S(O)n R8;
R5 is H, halo, C1-C6 alkyl, C1-C3 haloalkyl, C1-C6 alkoxy, (CHR16)pOR8, (CHR16)pNR14R15, C4-C6 cycloalkyl;
R6 and R7 are independently selected at each occurrence from the group consisting of:
C1-C6 alkyl, (CHR16)pR8;
or can be taken together to form xe2x80x94(CH2)qA (CH2)rxe2x80x94, optionally substituted with CH2OCH3;
A is CH2, O, S(O)n, N(C(xe2x95x90O)R18), N(R19), C(H) (OR20)
R8 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)tR22;
R9 is hydroxy, C1-C4 alkyl, or methoxy;
R13 is OR19, SR19, NR23R24, C3-C6 cycloalkyl;
R14 and R15 are independently is hydrogen, C1-C2 alkyl, C3-C6 cycloalkyl;
R16 is hydrogen;
R18 is hydrogen, C1-C4 alkyl, C1-C2 haloalkyl, C1-C4 alkoxy, C(xe2x95x90O)R24, or cyano; R19 is C1-C3 alkyl;
R20 is hydrogen, C1-C2 alkyl or C2-C3 alkenyl;
R22 is OR24;
R23 and R24 are independently selected at each occurrence from hydrogen or C1-C2 alkyl;
k is 1-3;
m is 1-4;
n is independently selected at each occurrence from 0-2;
p is 0-2;
q is 0-2;
r is 1-2;
t is independently selected at each occurrence from 1-3;
w is 1-3.
[4] Most preferred are those compounds of claim 1 selected from the group:
a) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;
b) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine;
c) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(N-propyl-N-cyclopropylmethylamino)-1,3,5-triazine;
d) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-homopiperidinyl)-1,3,5-triazine;
e) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(diethylamino)-1,3,5-triazine;
f) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(N-butyl-N-ethylamino)-1,3,5-triazine;
g) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazine;
h) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1-methoxybutyl)amino)-1,3,5-triazine;
i) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-piperidinyl)-1,3,5-triazine;
j) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(1.2.3.4-tetrahydroquinolinyl))-1,3,5-triazine;
k) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-pyrrolidinyl)-1,3,5triazine;
l) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(2-ethylpieridinyl))-1,3,5-triazine;
m) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1.2.3.4-tetrahydroisoquinolinyl))-1,3,5-triazine;
n) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(1,3,5,6-tetrahyropiperidinyl)-1,3,5-triazine;
o) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(2-trifluoromethylphenyl))-1,3,5-triazine;
p) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;
q) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine;
r) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(N-propyl-N-cyclopropylmethylamino)-1,3,5-triazine;
s) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(1-homopiperidinyl)-1,3,5-triazine;
t) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(N-butyl-N-ethylamino)-1,3,5-triazine;
u) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazine;
v) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-morpholinyl)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;
w) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;
x) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;
y) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(diethylamino)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;
z) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(1-piperidinyl)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;
aa) 3-Bromo-4-[[6-methyl-4(bis(2-methoxyethyl)amino )-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
bb) 3-Bromo-4-[[6-methyl-4(N-propyl-N-cyclopropylmethylamino)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
cc) 3-Bromo-4-[[6-methyl-4(2-(1-methoxybutyl)amino)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
dd) 3-Bromo-4-[[6-methyl-4(4-thiomormopholinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
ee) 3-Bromo-4-[[6-methyl-4(1-piperidinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
ff) 3-Bromo-4-[[6-methyl-4(1-homopiperidinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
gg) 3-Bromo-4-[[6-methyl-4(1-(2-trifluoromethylphenyl))-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
hh) 2-(2,4,6-Triodophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;
ii) 2-(2,4,6-Trichlorophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;
jj) 2-(2-chloro-4,6-Dimethoxyphenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine; and
kk) 2-[(2,6-Dibromo-4-(1-methylethyl))phenoxy]-4-methyl-6-(N-ethyl-N-butylamino)-1,3,5-triazine uu) 2-[(2,6-Dibromo-4-(1-methylethyl))phenoxy]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine.
[5] Also provided by this invention is method of treating affective disorders, anxiety, or depression in mammals comprising administering to the mammal a therapeutically effective amount of a compound provided herein.
[6] Also provided by this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound provided herein.
[7] The compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a pharmaceutical drug or other chemical compound to bind to the CRF receptor. These would be provided in commercial kits comprising a compound provided by this invention.